Trans metalated olefins (IIIB) add to 17-keto steroids (1) better than the corresponding cis isomers (IIIA) to produce 16-unsubstituted pregnanes (5) which can be readily converted by methods well known to those skilled in the art to useful 16-substituted corticoids. The metalated olefins (IIIA and IIIB) are prepared from the corresponding olefin (IIA and IIB). It therefore is important to be able to prepare the olefin (II) with a very high trans to cis ratio. The known methods for producing the olefins (II) produce mixtures with a very low trans to cis ratio, just the opposite of what is desired for the synthesis of the 16-unsubstituted pregnanes. The present invention solves this problem by producing the olefin (II) with a trans to cis ratio of greater than 70:30.
J. F. Arens et al. in Rec. trav. chim. 77, 753 (1958) disclose a process to convert chloroacetaldehyde diethylacetal to 1-chloro-2-ethoxyethene by heating with acid catalysts. On page 755 the authors indicate that "The product consisted for the greater part of the cis-isomer." The present invention surprisingly and unexpectedly produces a trans cis ratio of greater than 70:30.
J. F. Arens also reported in Rec. trav. chim. 74, 271 (1955) dehydrohalogenating 1,2-dichloro-2-ethoxyethane to give 1-chloro-2-ethoxyethene. On page 274 Arens indicates that the product contained ". . . about 75% of the cis isomer and 25% of the lower boiling trans isomer."
S. Hunig and M. Kiessel in Chem. Ber. 91, 380 (1958) reported transforming 1,2-dichloro-2-ethoxyethane to 1-chloro-2-ethoxyethene by use of a tertiary amine and heat. Under the various reaction conditions reported the reaction produced predominantly the cis isomer.
German Offen. 2,210,010 reports the reaction of 1,1-dichloro-2-methoxyethane with methoxide to give 1-chloro-2-methoxyethene. The cis isomer was produced (54%) to a greater extent than the trans isomer (46%).
D. A. VanDrop et al. reported in Rec. trav. chim. 70, 289 (1951) the conversion of dichloroacetaldehyde diethylacetal to 1-chloro-2-ethoxyethene by use of activated zinc dust. The authors report (page 293), "The yield of the cis-isomer is found to be 4-5 times as great as that of the trans-isomer, . . . ".
M. Farina et al. reported in Rend. 1st Lombardo Sci. Pt. 1 Classe Sci. Mat. e Nat. 94A, 600 (1960) that the transformation of 1,2-dichloro-2-i-butoxyethane to 1-chloro-2-i-butoxyethene with a tertiary amine and hydrochloric acid gave a product which contained 75-90% of the cis isomer.
All of the above articles indicate that the trans isomer is produced to a much less extent than the cis isomer. These were empirical findings and the possible mechanistic reasons were not reported. However, in 1976 E. Taskinen and E. Sainio in Tetrahedron 32, 593 (1976) reported that based on thermodynamic calculations the cis isomer should predominate due to its lower enthalpy.
Therefore, based on both theoretical considerations as well as previous experiments reported in the chemical literature one skilled in the art would expect to have a trans to cis ratio much less than 50:50. However, the present invention (process) surprisingly and unexpectedly produces 1-chloro-2-alkoxyethene (II) with a trans cis ratio of greater than 70:30.
The only other method known to produce a mixture of 1-chloro-2-alkoxyethene (II) which is enriched in the trans isomer to greater than a 70:30 ratio is an indirect one, namely, production of the cis trans mixture by old methods and then fractional distillation.